Journal
NATURE
Volume 570, Issue 7760, Pages 194-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-019-1232-1
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Funding
- Wellcome Trust [200523/Z/16/Z, 208385/Z/17/Z, 108466/Z/15/Z]
- Royal Society [200523/Z/16/Z]
- MRC [MC_PC-16050]
- NIH [R01 CA138835]
- Lupus Research Alliance
- BBSRC [BB/L021250/1, BB/E012558/1]
- BBSRC TDRF grant [BB/N021703/1]
- North West Cancer Research grants [CR1088, CR1097]
- Polish National Science Centre [2014/15/B/NZ1/03359]
- University of Leeds
- Biotechnology and Biological Sciences Research Council [BB/L021250/1, BB/E012558/1] Funding Source: researchfish
- Wellcome Trust [200523/Z/16/Z] Funding Source: researchfish
- BBSRC [BB/L021250/1, BB/E012558/1, BB/N021703/1, BB/S018514/1] Funding Source: UKRI
- MRC [MC_PC_16050] Funding Source: UKRI
- Wellcome Trust [200523/Z/16/Z] Funding Source: Wellcome Trust
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Serine hydroxymethyltransferase 2 (SHMT2) regulates one-carbon transfer reactions that are essential for amino acid and nucleotide metabolism, and uses pyridoxal-5'-phosphate (PLP) as a cofactor. Apo SHMT2 exists as a dimer with unknown functions, whereas PLP binding stabilizes the active tetrameric state. SHMT2 also promotes inflammatory cytokine signalling by interacting with the deubiquitylating BRCC36 isopeptidase complex (BRISC), although it is unclear whether this function relates to metabolism. Here we present the cryo-electron microscopy structure of the human BRISC-SHMT2 complex at a resolution of 3.8 A. BRISC is a U-shaped dimer of four subunits, and SHMT2 sterically blocks the BRCC36 active site and inhibits deubiquitylase activity. Only the inactive SHMT2 dimer-and not the active PLP-bound tetramer-binds and inhibits BRISC. Mutations in BRISC that disrupt SHMT2 binding impair type I interferon signalling in response to inflammatory stimuli. Intracellular levels of PLP regulate the interaction between BRISC and SHMT2, as well as inflammatory cytokine responses. These data reveal a mechanism in which metabolites regulate deubiquitylase activity and inflammatory signalling.
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